Periaqueductal gray astrocytes contribute to depression-pain comorbidity via the CXCL10/CXCR3 axis

Depression-pain comorbidity is a prevalent neuropsychiatric disorder with unclear pathogenic mechanisms. The periaqueductal gray (PAG) is one of the brain regions involved in emotional and pain processing. While astrocytes are known to be involved in various neurological disorders, their specific role in this comorbidity within the PAG is unclear. ​In this study, a mouse model of depression-pain comorbidity was established via chronic restraint stress (CRS). We found that CRS exposure induced marked depressive-like behaviors and mechanical allodynia in mice. This was accompanied by significant astrocyte activation and a corresponding upregulation of CXCL10 expression in the PAG. Chemogenetic inhibition of astrocyte activity alleviated these behavioral deficits. Furthermore, pharmacological blockade of the CXCL10 receptor, CXCR3, with AMG487 produced similar protective effects against CRS-induced abnormalities. Our findings demonstrate that astrocytes in the PAG contribute to chronic stress-induced depression-pain comorbidity through the CXCL10-CXCR3 signaling axis, identifying this pathway as a potential novel therapeutic target.